中文摘要

Cytochrome P450 1B1 （CYP1B1）是一種含有heme血素的單氧氧化?，在細胞內會代謝多種多環芳烴與芳香胺類化合物以及參與視黃酸與固醇類荷爾蒙的代謝。在哺乳動物體內，2.3.7.8-四氯二聯苯戴奧辛會透過AHR/ARNT細胞接受器的活化作用誘發CYP1B1基因在多種組織內的表現。在人類，CYP1B1基因亦參與了大腸直腸細胞與肺腺細胞癌化機轉以及先天性青光眼的遺傳性病變機制。我們在斑馬魚中找到與哺乳動物CYP1B1基因有高度相似性的基因。在胚胎孵化之前，斑馬魚CYP1B1基因專一性表現在中後腦中隔、間腦以及眼睛等部位。2.3.7.8-四氯二聯苯戴奧辛（TCDD）的處理並不會對這些部位原生性CYP1B1 mRNA的表現有明顯的影響，但是會在鰓弧、前腸以及心臟等部位誘發出新的CYP1B1 mRNA表現。利用反意morpholino寡核酸將胚胎內的AHR2基因弱化會抑制戴奧辛在鰓弧等處所誘發的CYP1B1 mRNA表現，但是對於眼睛等部位的原生性CYP1B1表現則不造成影響，顯示戴奧辛在鰓弧所引起的誘發性CYP1B1基因表現與正常胚胎在眼睛等部位的原生性CYP1B1表現是由不同的基因調控機制所控制。將CYP1B1基因弱化，並不會改變2.3.7.8-四氯二聯苯戴奧辛所造成的頭骨變形與心包膜膨大等生理毒性反應，顯示CYP1B1基因並未參與戴奧辛的毒性機轉。
CYP1C是魚類中CYP1新的次家族，在胚胎及成魚中基本表現在許多組織。就像其他CYP1家族成員，CYP1C可以被多環芳香碳氫化合物誘導產生基因表現。先前從斑馬魚胚胎中得到CYP1C1 cDNA （GenBank accession number AY_928186）。在late pharyngula時期斑馬魚CYP1C1開始基本表現在主動脈弧（aortic arches），在48-72小時間，有較高的原生性基因表現活性，接著表現逐漸減弱，TCDD曝露下CYP1C1的基因表現則明顯增強。雖然CYP1A1和CYP1C1均在胚胎血管中表現，但兩者表現形式各有不同，其中CYP1A1會表現在全身血管組織中而CYP1C1的表現則僅局限在主動脈弧的血管組織中，兩者對血管部位的選擇差異性有待未來進一步探討。
最後，為了探討斑馬魚內三種不同AHR對CYP1基因表現的功能，分別以反意morpholino弱化各AHR的轉譯後，探討各CYP1基因的表現情況。在CYP1C1基因方面，弱化AHR1A、AHR1B對CYP1C1基因表現僅引起輕微的影響，而弱化AHR2則完全抑制了原生性及TCDD所誘導產生的CYP1C1基因表現，顯示AHR2在CYP1C1基因表現中扮演重要的角色。在CYP1A1方面，弱化AHR1A轉譯後對CYP1A1並無明顯影響，而弱化AHR1B會降低血管部位原生性以及TCDD所誘導產生的CYP1A1表現，但仍維持眼睛部位的原生性CYP1A1基因表現。弱化AHR2則會完全抑制眼睛以外其他部位的原生性以及TCDD所誘導產生的CYP1A1基因表現。在CYP1B1方面，弱化AHR1A轉譯並不會對CYP1B1的表現產生影響，但是弱化AHR2則會明顯減弱但並未完全抑制眼睛部位的原生性CYP1B1表現，且可完全抑制TCDD所誘導之CYP1B1表現能力，顯示AHR2對原生性CYP1B1基因的表現相當重要，而對TCDD所誘導的CYP1B1基因表現能力則扮演不可或缺的功能。整體而言，雖然班馬魚中具有多種的AHR，但是其中僅有AHR2對調控CYP1的三種基因均扮演了關鍵性的角色。

Abstract

Cytochrome P450 1B1 （CYP1B1） is a heme-containing monooxygenase that metabolizes various polycyclic aromatic hydrocarbons （PAHs） and arylamines, as well as retinoic acid and steroid hormones. Here we presented that zebrafish CYP1B1 is constitutively expressed in embryonic ocular cells, diencephalons, and midbrain-hindbrain boundary during pharyngula stage. After hatching, the constitutive-type of CYP1B1 transcription is attenuated. TCDD exposure elicited de novo CYP1B1 transcription in pharyngeal arches and heart tissues at larval stage. Knockdown of AHR2 in zebrafish embryos abolished the induction of CYP1B1 by TCDD, but did not eliminate the basal level of CYP1B1 transcription in ocular cells. It suggests that the constitutive and TCDD-inducible types of CYP1B1 transcriptions are modulated by distinct pathways and exhibits different tissue specificity. We have also investigated the role of CYP1B1 in TCDD-mediated embryonic toxicity. Here we presented that CYP1B1 knockdown did not prevent TCDD-induced pericardial edema and cranial defects, suggesting that CYP1B1 does not involve in the developmental toxicity of dioxin.
CYP1C is a novel CYP1 subfamily that is constitutively expressed in a broad range of adult fish tissues and developing embryos. Like other CYP1 members, CYP1C genes can be induced by various polycyclic aromatic hydrocarbons. However, the pattern of CYP1C expression during early stages of development has not been fully addressed. Previously, we have cloned a complete CYP1C1 cDNA from zebrafish embryo （GenBank accession number AY_928186）. Here we reported that zebrafish CYP1C1 exhibited a restricted expression pattern dominantly in the vasculature of the aortic arches at late pharyngula stage. This basal type of transcription reached highest level at 48-72 hpf and subsequently its expression attenuated gradually. TCDD exposure elicited a high level of CYP1C1 transcription.
The function of AHR1A, AHR1B and AHR2 on CYP1 tanscription has also been investigated. Blocking AHR1A only had mild effects on TCDD-induced CYP1A1 and CYP1C1 transcription, but had no significant effect on CYP1B1 transcription. Knockdown AHR1B reduced both constitutive-type and TCDD-induced CYP1A1 transcription, but did not change CYP1C1 expression. Blocking AHR2 could completely inhibite TCDD-induced CYP1A1, CYP1B1 and CYP1C1 transcriptions and also reduced significant level of their constitute-type transcriptions in non-ocular tissues.

目錄
謝誌-------------------------------------------------------I
中文摘要 II
英文摘要 V
目錄 VII
壹、前言 1
一、Cytochrome P450 superfamily 1
二、芳香烴碳氫化合物接受器(aryl hydrocarbon receptor,AHR) 4
1、AHR訊息傳遞系統 7
2、AHR訊息傳遞負調控機制 11
三、戴奧辛 (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD) 12
四、肝臟外之CYPs 14
五、研究動機 17
貳、實驗材料與方法 18
一、實驗材料-------------------------------------------- 18
A、菌種及質體DNA 18
B、藥品---- 18
C、酵素及試劑 19
二、實驗方法--------------------------------------------- 21
A、斑馬魚飼養與受精胚胎收集--------------------------- 21
B、快速放大cDNA末端聚合?連鎖反應 22
C、DNA洋菜膠電泳--------------------------------------- 26
D、DNA分子之萃取--------------------------------------- 26
E、DNA接合反應----------------------------------------- 27
F、質體轉型 28
G、反轉錄聚合?連鎖反應-------------------------------- 28
H、RNA全覆式原位雜交-----------------------------------29
參、實 驗 結 果 33
一、 CYP1B1部分------------------------------------------ 33
1、CYP1B1基因選殖------------------------------------- 33
2、CYP1B1在斑馬魚胚胎的表現--------------------------- 33
3、TCDD誘發CYP1B1基因表現 34
4、CYP1B1基因表現的調節作用--------------------------- 35
5、CYP1B1之弱化無法清除TCDD所誘發的生理毒性----------- 36
二、CYP1C1部分-------------------------------------------- 36
1、CYP1C1在斑馬魚胚胎的表現----------------------------36
2、TCDD對CYP1C1基因表現量的影響------------------------37
3、AHR1A、AHR1B及AHR2在調節CYP1C1基因表現中所扮演的角色 37
4、AHR1A、AHR1B及AHR2在調節CYP1A基因表現中所扮演的角色 38
肆、實 驗 討 論 40
一、 CYP1B1部分 40
1、斑馬魚CYP1B1序列比對 40
2、種CYP1B1基因表現形式 41
3、孵化前CYP1B1基因的表現 41
4、孵化後經由AHR2的路徑誘發CYP1B1基因表現 42
5、CYP1B1未參與TCDD的毒性機轉 42
二、CYP1C1部分--------------------------------------------43
1、各CYP1基因表現的比較-------------------------------43
2、TCDD誘發CYP1基因表現的機制 44
3、斑馬魚各AHR基因弱化對胚胎時期CYP1基因家族的影響---44
伍、參考文獻--------------------------------------------- 46
陸、圖表------------------------------------------------- 60
表1、人類的CYP1A2、 CYP1B1和斑馬魚的CYP1B1在受質辨識
序列上胺基酸的比對
表2、斑馬魚各AHR基因弱化對胚胎時期CYP1基因家族的影響
Figure 1、 斑馬魚CYP1B1與其他動物CYP1B1序列比對
Figure 2、 斑馬魚正常胚胎在發育時期原生性及TCDD誘發型CYP1B1表現
形式
Figure 3、 ahr2反意寡核酸（ahr2 morpholino）有效抑制AHR2的轉譯作用
Figure 4、 弱化AHR2可以完全抑制TCDD所誘發CYP1B1的表現，但無法
完全抑制原生性CYP1B1的表現
Figure 5、 使CYP1B1弱化（knockdown）無法阻止TCDD所誘發的生理毒害
Figure 6、 斑馬魚正常胚胎在發育時期原生性及TCDD所誘發CYP1C1的表現形式
Figure 7、 將AHR1A弱化後，觀察原生性CYP1C1的表現
Figure 8、 AHR1A弱化後，由TCDD所誘發的CYP1C1基因表現僅受到輕微的影響
Figure 9. AHR1B弱化，在96小時的斑馬魚胚胎中原生性CYP1C1表現增加
Figure 10. 將AHR1B弱化，由TCDD所誘發的CYP1C1表現沒有明顯抑制
Figure 11. AHR2弱化後的斑馬魚胚胎，幾乎完全抑制CYP1C1的原生性表現
Figure 12. 將AHR2弱化，幾乎完全抑制TCDD所誘發CYP1C1的基因表現
Figure 13. 將AHR1A弱化，觀察原生性CYP1A1的表現
Figure 14. 將AHR1A弱化，由TCDD所誘發的CYP1A1表現有些微的影響
Figure 15. AHR1B弱化後，原生性CYP1A1的表現明顯減弱
Figure 16. AHR1B弱化，TCDD所誘發的CYP1A1表現減少
Figure 17. 將AHR2弱化，除了眼睛外，幾乎完全抑制原生性CYP1A1的表現能力
Figure 18. 將AHR2弱化，除了眼睛外，幾乎完全抑制TCDD所誘發的CYP1A1表現
Figure 19. 將AHR1A弱化，並未影響原生性CYP1B1或TCDD所誘發的CYP1B1表現
Figure 20. 比較斑馬魚AHR1A弱化對胚胎發育時期CYP1基因家族的影響
Figure 21. 比較斑馬魚AHR1B弱化對胚胎發育時期CYP1基因家族的影響
Figure 22. 比較斑馬魚AHR2弱化對胚胎發育時期CYP1基因家族的影響

附件-----------------------------------------------------84
Influence of TCDD on Zebrafish CYP1B1Transcription during Development

伍、參考文獻

Abbott, B. D., Schmid, J. E., Pitt, J. A., Buckalew, A. R., Wood, C. R., Held, G. A. and Diliberto, J. J. (1999). Adverse reproductive outcomes in the transgenic Ah receptor-deficient mouse. Toxicol Appl Pharmacol 155, 62-70.

Abnet, C. C., Tanguay, R. L., Hahn, M. E., Heideman, W. and Peterson, R. E. (1999a). Two forms of aryl hydrocarbon receptor type 2 in rainbow trout (Oncorhynchus mykiss). Evidence for differential expression and enhancer specificity. Journal of Biological Chemistry 274, 15159-15166.

Abnet, C. C., Tanguay, R. L., Heideman, W. and Peterson, R. E. (1999b). Transactivation activity of human, zebrafish, and rainbow trout aryl hydrocarbon receptors expressed in COS-7 cells: greater insight into species differences in toxic potency of polychlorinated dibenzo-p-dioxin, dibenzofuran, and biphenyl congeners. Toxicol Appl Pharmacol 159, 41-51.

Adachi, J., Mori, Y., Matsui, S., Takigami, H., Fujino, J., Kitagawa, H., Miller, C. A., 3rd, Kato, T., Saeki, K. and Matsuda, T. (2001). Indirubin and indigo are potent aryl hydrocarbon receptor ligands present in human urine. Journal of Biological Chemistry 276, 31475-31478.

Anderson, J. W., Rossi, S. S., Tukey, R. H., Vu, T. and Quattrochi, L. C. (1995). A biomarker, P450 RGS, for assessing the induction potential of environmental samples. Environ Toxicol Pharmacol 14, 1159-1169.

Andreasen, E. A., Hahn, M. E., Heideman, W., Peterson, R. E. and Tanguay, R. L. (2002a). The zebrafish (Danio rerio) aryl hydrocarbon receptor type 1 is a novel vertebrate receptor. Molecular Pharmacology 62, 234-249.

Andreasen, E. A., Spitsbergen, J. M., Tanguay, R. L., Stegeman, J. J., Heideman, W. and Peterson, R. E. (2002b). Tissue-specific expression of AHR2, ARNT2, and CYP1A in zebrafish embryos and larvae: effects of developmental stage and 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure. Toxicol Sci 68, 403-419.

Andreola, F., Fernandez-Salguero, P. M., Chiantore, M. V., Petkovich, M. P., Gonzalez, F. J. and De Luca, L. M. (1997). Aryl hydrocarbon receptor knockout mice (AHR-/-) exhibit liver retinoid accumulation and reduced retinoic acid metabolism. Cancer Res 57, 2835-2838.

Antkiewicz, D. S., Peterson, R. E. and Heideman, W. (2006). Blocking expression of AHR2 and ARNT1 in zebrafish larvae protects against cardiac toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Sci 94, 175-182.

Benedict, J. C., Lin, T. M., Loeffler, I. K., Peterson, R. E. and Flaws, J. A. (2000). Physiological role of the aryl hydrocarbon receptor in mouse ovary development. Toxicological Sciences 56, 382-388.
Bhagwat, S. V., Boyd, M. R. and Ravindranath, V. (2000). Multiple forms of cytochrome P450 and associated monooxygenase activities in human brain mitochondria. Biochem Pharmacol 59, 573-582.

Billiard, S. M., Timme-Laragy, A. R., Wassenberg, D. M., Cockman, C. and Di Giulio, R. T. (2006). The role of the aryl hydrocarbon receptor pathway in mediating synergistic developmental toxicity of polycyclic aromatic hydrocarbons to zebrafish. Toxicol Sci 92, 526-536.

Boutelet-Bochan, H., Huang, Y. and Juchau, M. R. (1997). Expression of CYP2E1 during embryogenesis and fetogenesis in human cephalic tissues: implications for the fetal alcohol syndrome. Biochem Biophys Res Commun 238, 443-447.

Burbach, K. M., Poland, A. and Bradfield, C. A. (1992). Cloning of the Ah-receptor cDNA reveals a distinctive ligand-activated transcription factor. Proc Natl Acad Sci U S A 89, 8185-8189.

Buters, J. T., Doehmer, J. and Gonzalez, F. J. (1999a). Cytochrome P450-null mice. Drug Metab Rev 31, 437-447.

Buters, J. T., Sakai, S., Richter, T., Pineau, T., Alexander, D. L., Savas, U., Doehmer, J., Ward, J. M., Jefcoate, C. R. and Gonzalez, F. J. (1999b). Cytochrome P450 CYP1B1 determines susceptibility to 7, 12-dimethylbenz[a]anthracene-induced lymphomas. Proc Natl Acad Sci U S A 96, 1977-1982.

Brzezinski, M. R., Boutelet-Bochan, H., Person, R. E., Fantel, A. G. and Juchau, M. R. (1999). Catalytic activity and quantitation of cytochrome P-450 2E1 in prenatal human brain. J Pharmacol Exp Ther 289, 1648-1653.

Cantrell, S. M., Joy-Schlezinger, J., Stegeman, J. J., Tillitt, D. E. and Hannink, M. (1998). Correlation of 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced apoptotic cell death in the embryonic vasculature with embryotoxicity. Toxicol Appl Pharmacol 148, 24-34.

Carney, S. A., Chen, J., Burns, C. G., Xiong, K. M., Peterson, R. E. and Heideman, W. (2006a). Aryl hydrocarbon receptor activation produces heart-specific transcriptional and toxic responses in developing zebrafish. Mol Pharmacol 70, 549-561.

Carney, S. A., Peterson, R. E. and Heideman, W. (2004). 2,3,7,8-Tetrachlorodibenzo-p-dioxin activation of the aryl hydrocarbon receptor/aryl hydrocarbon receptor nuclear translocator pathway causes developmental toxicity through a CYP1A-independent mechanism in zebrafish. Mol Pharmacol 66, 512-521.

Carney, S. A., Prasch, A. L., Heideman, W. and Peterson, R. E. (2006b). Understanding dioxin developmental toxicity using the zebrafish model. Birth Defects Res A Clin Mol Teratol 76, 7-18.

Carvan, M. J., 3rd, Dalton, T. P., Stuart, G. W. and Nebert, D. W. (2000). Transgenic zebrafish as sentinels for aquatic pollution. Ann N Y Acad Sci 919, 133-147.

Carver, L. A. and Bradfield, C. A. (1997). Ligand-dependent interaction of the aryl hydrocarbon receptor with a novel immunophilin homolog in vivo. Journal of Biological Chemistry 272, 11452-11456.

Chan, W. K., Yao, G., Gu, Y. Z. and Bradfield, C. A. (1999). Cross-talk between the aryl hydrocarbon receptor and hypoxia inducible factor signaling pathways. Demonstration of competition and compensation. Journal of Biological Chemistry 274, 12115-12123.

Chen, H., Howald, W. N. and Juchau, M. R. (2000). Biosynthesis of all-trans-retinoic acid from all-trans-retinol: catalysis of all-trans-retinol oxidation by human P-450 cytochromes. Drug Metab Dispos 28, 315-322.

Choudhary, D., Jansson, I., Sarfarazi, M. and Schenkman, J. B. (2004). Xenobiotic-metabolizing cytochromes P450 in ontogeny: evolving perspective. Drug Metab Rev 36, 549-568.

Coumailleau, P., Poellinger, L., Gustafsson, J. A. and Whitelaw, M. L. (1995). Definition of a minimal domain of the dioxin receptor that is associated with Hsp90 and maintains wild type ligand binding affinity and specificity. Journal of Biological Chemistry 270, 25291-25300.

Crews, S. T. (1998). Control of cell lineage-specific development and transcription by bHLH-PAS proteins. Genes Dev 12, 607-20.
6
Crews, S. T. and Fan, C. M. (1999). Remembrance of things PAS: regulation of development by bHLH-PAS proteins. Curr Opin Genet Dev 9, 580-587.

Davarinos, N. A. and Pollenz, R. S. (1999). Aryl hydrocarbon receptor imported into the nucleus following ligand binding is rapidly degraded via the cytosplasmic proteasome following nuclear export. Journal of Biological Chemistry 274, 28708-28715.

Dey, A., Jones, J. E. and Nebert, D. W. (1999). Tissue- and cell type-specific expression of cytochrome P450 1A1 and cytochrome P450 1A2 mRNA in the mouse localized in situ hybridization. Biochem Pharmacol 58, 525-537.

Eltom, S. E., Larsen, M. C. and Jefcoate, C. R. (1998). Expression of CYP1B1 but not CYP1A1 by primary cultured human mammary stromal fibroblasts constitutively and in response to dioxin exposure: role of the Ah receptor. Carcinogenesis 19, 1437-1444.

Eltom, S. E., Zhang, L. and Jefcoate, C. R. (1999). Regulation of cytochrome P-450 (CYP) 1B1 in mouse Hepa-1 variant cell lines: A possible role for aryl hydrocarbon receptor nuclear translocator (ARNT) as a suppressor of CYP1B1 gene expression. Mol Pharmacol 55, 594-604.

Ema, M., Sogawa, K., Watanabe, N., Chujoh, Y., Matsushita, N., Gotoh, O., Funae, Y. and Fujii-Kuriyama, Y. (1992). cDNA cloning and structure of mouse putative Ah receptor. Biochem Biophys Res Commun 184, 246-253.

Evans, B. R., Karchner, S. I., Franks, D. G. and Hahn, M. E. (2005). Duplicate aryl hydrocarbon receptor repressor genes (ahrr1 and ahrr2) in the zebrafish Danio rerio: structure, function, evolution, and AHR-dependent regulation in vivo. Arch Biochem Biophys 441, 151-167.

Farin, F. M. and Omiecinski, C. J. (1993). Regiospecific expression of cytochrome P-450s and microsomal epoxide hydrolase in human brain tissue. J Toxicol Environ Health 40, 317-335.

Fernandez-Salguero, P., Pineau, T., Hilbert, D. M., McPhail, T., Lee, S. S., Kimura, S., Nebert, D. W., Rudikoff, S., Ward, J. M. and Gonzalez, F. J. (1995). Immune system impairment and hepatic fibrosis in mice lacking the dioxin-binding Ah receptor. Science 268, 722-726.

Fernandez-Salguero, P. M., Ward, J. M., Sundberg, J. P. and Gonzalez, F. J. (1997). Lesions of aryl-hydrocarbon receptor-deficient mice. Vet Pathol 34, 605-614.

Fujisawa-Sehara, A., Sogawa, K., Yamane, M. and Fujii-Kuriyama, Y. (1987). Characterization of xenobiotic responsive elements upstream from the drug-metabolizing cytochrome P-450c gene: a similarity to glucocorticoid regulatory elements. Nucleic Acids Res 15, 4179-4191.

Fukunaga, B. N. and Hankinson, O. (1996). Identification of a novel domain in the aryl hydrocarbon receptor required for DNA binding. Journal of Biological Chemistry 271, 3743-1749.

Fukunaga, B. N., Probst, M. R., Reisz-Porszasz, S. and Hankinson, O. (1995). Identification of functional domains of the aryl hydrocarbon receptor. Journal of Biological Chemistry 270, 29270-29278.

Giannone, J. V., Li, W., Probst, M. and Okey, A. B. (1998). Prolonged depletion of AH receptor without alteration of receptor mRNA levels after treatment of cells in culture with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Biochem Pharmacol 55, 489-497.

Godard, C. A., Goldstone, J. V., Said, M. R., Dickerson, R. L., Woodin, B. R. and Stegeman, J. J. (2005). The new vertebrate CYP1C family: cloning of new subfamily members and phylogenetic analysis. Biochem Biophys Res Commun 331, 1016-1024.

Gonzalez, F. J. and Kimura, S. (2003). Study of P450 function using gene knockout and transgenic mice. Arch Biochem Biophys 409, 153-158.

Gradin, K., McGuire, J., Wenger, R. H., Kvietikova, I., fhitelaw, M. L., Toftgard, R., Tora, L., Gassmann, M. and Poellinger, L. (1996). Functional interference between hypoxia and dioxin signal transduction pathways: competition for recruitment of the Arnt transcription factor. Mol Cell Biol 16, 5221-5231.

Gervot, L., Rochat, B., Gautier, J. C., Bohnenstengel, F., Kroemer, H., de Berardinis, V., Martin, H., Beaune, P. and de Waziers, I. (1999). Human CYP2B6: expression, inducibility and catalytic activities. Pharmacogenetics 9, 295-306.

Ghersi-Egea, J. F., Leninger-Muller, B., Suleman, G., Siest, G. and Minn, A. (1994). Localization of drug-metabolizing enzyme activities to blood-brain interfaces and circumventricular organs. J Neurochem 62, 1089-1096.

Gradin, K., Toftgard, R., Poellinger, L. and Berghard, A. (1999). Repression of dioxin signal transduction in fibroblasts. Identification Of a putative repressor associated with Arnt. Journal of Biological Chemistry 274, 13511-13518.

Gu, Y. Z., Hogenesch, J. B. and Bradfield, C. A. (2000). The PAS superfamily: sensors of environmental and developmental signals. Annu Rev Pharmacol Toxicol 40, 519-561.

Guengerich, F. P. (2003). Cytochromes P450, drugs, and diseases. Mol Interv 3, 194-204.
Guengerich, F. P., Johnson, W. W., Ueng, Y. F., Yamazaki, H. and Shimada, T. (1996). Involvement of cytochrome P450, glutathione S-transferase, and epoxide hydrolase in the metabolism of aflatoxin B1 and relevance to risk of human liver cancer. Environ Health Perspect 104 Suppl 3, 557-562.

Guiney, P. D., Smolowitz, R. M., Peterson, R. E. and Stegeman, J. J. (1997). Correlation of 2,3,7,8-tetrachlorodibenzo-p-dioxin induction of cytochrome P4501A in vascular endothelium with toxicity in early life stages of lake trout. Toxicol Appl Pharmacol 143, 256-273.

Guiney, P. D., Walker, M. K., Spitsbergen, J. M. and Peterson, R. E. (2000). Hemodynamic dysfunction and cytochrome P4501A mRNA expression induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin during embryonic stages of lake trout development. Toxicol Appl Pharmacol 168, 1-14.

Hahn, M. E., Karchner, S. I., Shapiro, M. A. and Perera, S. A. (1997). Molecular evolution of two vertebrate aryl hydrocarbon (dioxin) receptors (AHR1 and AHR2) and the PAS family. Proc Natl Acad Sci U S A 94, 13743-13748.

Handley-Goldstone, H. M., Grow, M. W. and Stegeman, J. J. (2005). Cardiovascular gene expression profiles of dioxin exposure in zebrafish embryos. Toxicol Sci 85, 683-693.

Hankinson, S. E., Colditz, G. A., Hunter, D. J., Willett, W. C., Stampfer, M. J., Rosner, B., Hennekens, C. H. and Speizer, F. E. (1995). A prospective study of reproductive factors and risk of epithelial ovarian cancer. Cancer 76, 284-290.

Heath-Pagliuso, S., Rogers, W. J., Tullis, K., Seidel, S. D., Cenijn, P. H., Brouwer, A. and Denison, M. S. (1998). Activation of the Ah receptor by tryptophan and tryptophan metabolites. Biochemistry 37, 11508-11515.

Hedlund, E., Wyss, A., Kainu, T., Backlund, M., Kohler, C., Pelto-Huikko, M., Gustafsson, J. A. and Warner, M. (1996). Cytochrome P4502D4 in the brain: specific neuronal regulation by clozapine and toluene. Mol Pharmacol 50, 342-350.

Heid, S. E., Pollenz, R. S. and Swanson, H. I. (2000). Role of heat shock protein 90 dissociation in mediating agonist-induced activation of the aryl hydrocarbon receptor. Molecular Pharmacology 57, 82-92.

Heimler, I., Trewin, A. L., Chaffin, C. L., Rawlins, R. G. and Hutz, R. J. (1998). Modulation of ovarian follicle maturation and effects on apoptotic cell death in Holtzman rats exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in utero and lactationally. Reprod Toxicol 12, 69-73.

Henry, T. R., Spitsbergen, J. M., Hornung, M. W., Abnet, C. C. and Peterson, R. E. (1997). Early life stage toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in zebrafish (Danio rerio). Toxicol Appl Pharmacol 142, 56-68.

Hoffman, E. C., Reyes, H., Chu, F. F., Sander, F., Conley, L. H., Brooks, B. A. and Hankinson, O. (1991). Cloning of a factor required for activity of the Ah (dioxin) receptor. Science 252, 954-958.

Hukkanen, J., Pelkonen, O., Hakkola, J. and Raunio, H. (2002). Expression and regulation of xenobiotic-metabolizing cytochrome P450 (CYP) enzymes in human lung. Crit Rev Toxicol 32, 391-411.

Hushka, L. J., Williams, J. S. and Greenlee, W. F. (1998). Characterization of 2,3,7,8-Tetrachlorodibenzofuran-Dependent Suppression and AH Receptor Pathway Gene Expression in the Developing Mouse Mammary Gland. Toxicol Appl Pharmacol 152, 200-210.

Ikegwuonu, F. I., Ganem, L. G., Larson, M. C., Shen, X. and Jefcoate, C. R. (1996). The regulation by gender, strain, dose, and feeding status of the induction of multiple forms of cytochrome P450 isozymes in rat hepatic microsomes by 2,4,5,2',4',5'-hexachlorobiphenyl. Toxicol Appl Pharmacol 139, 33-41.

Ikuta, T., Eguchi, H., Tachibana, T., Yoneda, Y. and Kawajiri, K. (1998). Nuclear localization and export signals of the human aryl hydrocarbon receptor. Journal of Biological Chemistry 273, 2895-2904.

Ilian, M. A., Sparrow, B. R., Ryu, B. W., Selivonchick, D. P. and Schaup, H. W. (1996). Expression of hepatic pyruvate carboxylase mRNA in C57BL/6J Ah(b/b) and congenic Ah((d/d)) mice exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. J Biochem Toxicol 11, 51-56.
Janmohamed, A., Dolphin, C. T., Phillips, I. R. and Shephard, E. A. (2001). Quantification and cellular localization of expression in human skin of genes encoding flavin-containing monooxygenases and cytochromes P450. Biochem Pharmacol 62, 777-86
Jones, P. B., Durrin, L. K., Galeazzi, D. R. and Whitlock, J. P., Jr. (1985). Control of cytochrome P1-450 gene expression by dioxin. Science 227, 1499-1502.

Jones, P. B., Durrin, L. K., Galeazzi, D. R. and Whitlock, J. P., Jr. (1986). Control of cytochrome P1-450 gene expression: analysis of a dioxin-responsive enhancer system. Proc Natl Acad Sci U S A 83, 2802-2806.

Jonsson, M. E., Jenny, M. J., Woodin, B. R., Hahn, M. E. and Stegeman, J. J. (2007). Role of AHR2 in the expression of novel cytochrome P450 1 family genes, cell cycle genes, and morphological defects in developing zebra fish exposed to 3,3',4,4',5-pentachlorobiphenyl or 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Sci 100, 180-193.

Karchner, S. I., Franks, D. G. and Hahn, M. E. (2005). AHR1B, a new functional aryl hydrocarbon receptor in zebrafish: tandem arrangement of ahr1b and ahr2 genes. Biochem J 392, 153-161.

Karchner, S. I., Powell, W. H. and Hahn, M. E. (1999). Identification and functional characterization of two highly divergent aryl hydrocarbon receptors (AHR1 and AHR2) in the teleost Fundulus heteroclitus. Evidence for a novel subfamily of ligand-binding basic helix loop helix-Per-ARNT-Sim (bHLH-PAS) factors. J Biol Chem 274, 33814-3324.

Kazlauskas, A., Poellinger, L. and Pongratz, I. (1999). Evidence that the co-chaperone p23 regulates ligand responsiveness of the dioxin (Aryl hydrocarbon) receptor. Journal of Biological Chemistry 274, 13519-13524.

Kerzee, J. K. and Ramos, K. S. (2001). Constitutive and inducible expression of CYP1A1 and CYP1B1 in vascular smooth muscle cells: role of the Ahr bHLH/PAS transcription factor. Circ Res 89, 573-582.

Klose, T. S., Blaisdell, J. A. and Goldstein, J. A. (1999). Gene structure of CYP2C8 and extrahepatic distribution of the human CYP2Cs. J Biochem Mol Toxicol 13, 289-295.

Krishnan, V., Porter, W., Santostefano, M., Wang, X. and Safe, S. (1995). Molecular mechanism of inhibition of estrogen-induced cathepsin D gene expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in MCF-7 cells. Mol Cell Biol 15, 6710-6719.

Kubota, M., Sogawa, K., Kaizu, Y., Sawaya, T., Watanabe, J., Kawajiri, K., Gotoh, O. and Fujii-Kuriyama, Y. (1991). Xenobiotic responsive element in the 5'-upstream region of the human P-450c gene. J Biochem 110, 232-236.

Lahvis, G. P. and Bradfield, C. A. (1998). Ahr null alleles: distinctive or different? Biochem Pharmacol 56, 781-787.

Lees, M. J. and Whitelaw, M. L. (1999). Multiple roles of ligand in transforming the dioxin receptor to an active basic helix-loop-helix/PAS transcription factor complex with the nuclear protein Arnt. Mol Cell Biol 19, 5811-5822.

Lewis, D. F., Lake, B. G., George, S. G., Dickins, M., Eddershaw, P. J., Tarbit, M. H., Beresford, A. P., Goldfarb, P. S. and Guengerich, F. P. (1999). Molecular modelling of CYP1 family enzymes CYP1A1, CYP1A2, CYP1A6 and CYP1B1 based on sequence homology with CYP102. Toxicology 139, 53-79.

Lewis, D. F. V., Gillam, E. M. J., Everett, S. A. and Shimada, T. (2003). Molecular modelling of human CYP1B1 substrate interactions and investigation of allelic variant effects on metabolism. Chemico-Biological Interactions 145, 281-295.

Lewis, J. S., Thomas, T. J., Klinge, C. M., Gallo, M. A. and Thomas, T. (2001). Regulation of cell cycle and cyclins by 16alpha-hydroxyestrone in MCF-7 breast cancer cells. J Mol Endocrinol 27, 293-307.

Lindebro, M. C., Poellinger, L. and Whitelaw, M. L. (1995). Protein-protein interaction via PAS domains: role of the PAS domain in positive and negative regulation of the bHLH/PAS dioxin receptor-Arnt transcription factor complex. Embo J 14, 3528-3539.

Luch, A., Schober, W., Soballa, V. J., Raab, G., Greim, H., Jacob, J., Doehmer, J. and Seidel, A. (1999). Metabolic activation of dibenzo[a,l]pyrene by human cytochrome P450 1A1 and P450 1B1 expressed in V79 Chinese hamster cells. Chem Res Toxicol 12, 353-364.

Luo, G., Zeldin, D. C., Blaisdell, J. A., Hodgson, E. and Goldstein, J. A. (1998). Cloning and expression of murine CYP2Cs and their ability to metabolize arachidonic acid. Arch Biochem Biophys 357, 45-57.

Ma, Q. and Whitlock, J. P., Jr. (1997). A novel cytoplasmic protein that interacts with the Ah receptor, contains tetratricopeptide repeat motifs, and augments the transcriptional response to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Journal of Biological Chemistry 272, 8878-8884.

Ma, Q. and Whitlock, J. P., Jr. (1996). The aromatic hydrocarbon receptor modulates the Hepa 1c1c7 cell cycle and differentiated state independently of dioxin. Mol Cell Biol 16, 2144-2150.

McFayden, M. C., Melvin, W. T. and Murray, G. I. (1998). Regional distribution of individual forms of cytochrome P450 mRNA in normal adult human brain. Biochem Pharmacol 55, 825-830.

McGuire, J., Whitelaw, M. L., Pongratz, I., Gustafsson, J. A. and Poellinger, L. (1994). A cellular factor stimulates ligand-dependent release of hsp90 from the basic helix-loop-helix dioxin receptor. Mol Cell Biol 14, 2438-2446.

Meyer, B. K. and Perdew, G. H. (1999). Characterization of the AhR-hsp90-XAP2 core complex and the role of the immunophilin-related protein XAP2 in AhR stabilization. Biochemistry 38, 8907-8917.

Meyer, B. K., Pray-Grant, M. G., Vanden Heuvel, J. P. and Perdew, G. H. (1998). Hepatitis B virus X-associated protein 2 is a subunit of the unliganded aryl hydrocarbon receptor core complex and exhibits transcriptional enhancer activity. Mol Cell Biol 18, 978-988.

Miksys, S., Rao, Y., Hoffmann, E., Mash, D. C. and Tyndale, R. F. (2002). Regional and cellular expression of CYP2D6 in human brain: higher levels in alcoholics. J Neurochem 82, 1376-1387.

Miksys, S., Rao, Y., Sellers, E. M., Kwan, M., Mendis, D. and Tyndale, R. F. (2000). Regional and cellular distribution of CYP2D subfamily members in rat brain. Xenobiotica 30, 547-564.

Mimura, J., Ema, M., Sogawa, K. and Fujii-Kuriyama, Y. (1999). Identification of a novel mechanism of regulation of Ah (dioxin) receptor function. Genes Dev 13(1), 20-5.
Mimura, J. and Fujii-Kuriyama, Y. (2003). Functional role of AhR in the expression of toxic effects by TCDD. Biochim Biophys Acta 1619, 263-268.

Morse, D. C., Stein, A. P., Thomas, P. E. and Lowndes, H. E. (1998). Distribution and induction of cytochrome P450 1A1 and 1A2 in rat brain. Toxicol Appl Pharmacol 152, 232-239.

Muskhelishvili, L., Thompson, P. A., Kusewitt, D. F., Wang, C. and Kadlubar, F. F. (2001). In situ hybridization and immunohistochemical analysis of cytochrome P450 1B1 expression in human normal tissues. J Histochem Cytochem 49, 229-236.

Nambu, J. R., Lewis, J. O., Wharton, K. A., Jr. and Crews, S. T. (1991). The Drosophila single-minded gene encodes a helix-loop-helix protein that acts as a master regulator of CNS midline development. Cell 67, 1157-1167.

Nebert, D. W., Puga, A. and Vasiliou, V. (1993). Role of the Ah receptor and the dioxin-inducible [Ah] gene battery in toxicity, cancer, and signal transduction. Ann N Y Acad Sci 685, 624-640.

Nebert, D. W., Roe, A. L., Dieter, M. Z., Solis, W. A., Yang, Y. and Dalton, T. P. (2000). Role of the aromatic hydrocarbon receptor and [Ah] gene battery in the oxidative stress response, cell cycle control, and apoptosis. Biochem Pharmacol 59, 65-85.

Nelson, D. R. (1999). Cytochrome P450 and the individuality of species. Arch Biochem Biophys 369, 1-10.

Nie, M., Blankenship, A. L. and Giesy, J. P. (2001). Interactions between aryl hydrocarbon receptor (AhR) and hypoxia signaling pathways. Environ Toxicol Pharmacol 10, 17-27.

Pasanen, M. and Pelkonen, O. (1994). The expression and environmental regulation of P450 enzymes in human placenta. Crit Rev Toxicol 24, 211-229.

Peterson, R. E., Theobald, H. M. and Kimmel, G. L. (1993). Developmental and reproductive toxicity of dioxins and related compounds: cross-species comparisons. Crit Rev Toxicol 23, 283-295.

Pini, B., Grosser, T., Lawson, J. A., Price, T. S., Pack, M. A. and FitzGerald, G. A. (2005). Prostaglandin E synthases in zebrafish. Arterioscler Thromb Vasc Biol 25, 315-320.

Pitt, J. A., Feng, L., Abbott, B. D., Schmid, J., Batt, R. E., Costich, T. G., Koury, S. T. and Bofinger, D. P. (2001). Expression of AhR and ARNT mRNA in cultured human endometrial explants exposed to TCDD. Toxicol Sci 62, 289-298.

Poland, A. and Knutson, J. C. (1982). 2,3,7,8-tetrachlorodibenzo-p-dioxin and related halogenated aromatic hydrocarbons: examination of the mechanism of toxicity. Annu Rev Pharmacol Toxicol 22, 517-554.

Pollenz, R. S. (1996). The aryl-hydrocarbon receptor, but not the aryl-hydrocarbon receptor nuclear translocator protein, is rapidly depleted in hepatic and nonhepatic culture cells exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Molecular Pharmacology 49, 391-398.

Pollenz, R. S. (2002). The mechanism of AH receptor protein down-regulation (degradation) and its impact on AH receptor-mediated gene regulation. Chem Biol Interact 141, 41-61.

Pollenz, R. S. and Buggy, C. (2006). Ligand-dependent and -independent degradation of the human aryl hydrocarbon receptor (hAHR) in cell culture models. Chem Biol Interact 164, 49-59.

Postlind, H., Vu, T. P., Tukey, R. H. and Quattrochi, L. C. (1993). Response of human CYP1-luciferase plasmids to 2,3,7,8-tetrachlorodibenzo-p-dioxin and polycyclic aromatic hydrocarbons. Toxicol Appl Pharmacol 118, 255-262.

Prasch, A. L., Tanguay, R. L., Mehta, V., Heideman, W. and Peterson, R. E. (2006). Identification of zebrafish ARNT1 homologs: 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity in the developing zebrafish requires ARNT1. Mol Pharmacol 69, 776-787.

Prasch, A. L., Teraoka, H., Carney, S. A., Dong, W., Hiraga, T., Stegeman, J. J., Heideman, W. and Peterson, R. E. (2003). Aryl hydrocarbon receptor 2 mediates 2,3,7,8-tetrachlorodibenzo-p-dioxin developmental toxicity in zebrafish. Toxicol Sci 76, 138-150.

Rieder, C. R., Parsons, R. B., Fitch, N. J., Williams, A. C. and Ramsden, D. B. (2000). Human brain cytochrome P450 1B1: immunohistochemical localization in human temporal lobe and induction by dimethylbenz(a)anthracene in astrocytoma cell line (MOG-G-CCM). Neurosci Lett 278, 177-180.
Rieder, C. R., Ramsden, D. B. and Williams, A. C. (1998). Cytochrome P450 1B1 mRNA in the human central nervous system. Mol Pathol 51, 138-142.

Riedl, A. G., Watts, P. M., Douek, D. C., Edwards, R. J., Boobis, A. R., Rose, S. and Jenner, P. (2000). Expression and distribution of CYP2C enzymes in rat basal ganglia. Synapse 38, 392-402.

Riedl, A. G., Watts, P. M., Edwards, R. J., Schulz-Utermoehl, T., Boobis, A. R., Jenner, P. and Marsden, C. D. (1999). Expression and localisation of CYP2D enzymes in rat basal ganglia. Brain Res 822, 175-191.

Rowlands, J. C. and Gustafsson, J. A. (1997). Aryl hydrocarbon receptor-mediated signal transduction. Crit Rev Toxicol 27, 109-134.

Roy, N. K. and Wirgin, I. (1997). Characterization of the aromatic hydrocarbon receptor gene and its expression in Atlantic tomcod. Arch Biochem Biophys 344, 373-386.

Sansen, S., Yano, J. K., Reynald, R. L., Schoch, G. A., Griffin, K. J., Stout, C. D. and Johnson, E. F. (2007). Adaptations for the oxidation of polycyclic aromatic hydrocarbons exhibited by the structure of human P450 1A2. J Biol Chem 282, 14348-14355.

Savas, U., Bhattacharyya, K. K., Christou, M., Alexander, D. L. and Jefcoate, C. R. (1994). Mouse cytochrome P-450EF, representative of a new 1B subfamily of cytochrome P-450s. Cloning, sequence determination, and tissue expression. J Biol Chem 269, 14905-14911.

Schilter, B. and Omiecinski, C. J. (1993). Regional distribution and expression modulation of cytochrome P-450 and epoxide hydrolase mRNAs in the rat brain. Mol Pharmacol 44, 990-996.

Schlezinger, J. J., White, R. D. and Stegeman, J. J. (1999). Oxidative inactivation of cytochrome P-450 1A (CYP1A) stimulated by 3,3',4,4'-tetrachlorobiphenyl: production of reactive oxygen by vertebrate CYP1As. Molecular Pharmacology 56, 588-597.

Schmidt, J. V. and Bradfield, C. A. (1996). Ah receptor signaling pathways. Annu Rev Cell Dev Biol 12, 55-89.

Schmidt, J. V., Su, G. H., Reddy, J. K., Simon, M. C. and Bradfield, C. A. (1996). Characterization of a murine Ahr null allele: involvement of the Ah receptor in hepatic growth and development. Proc Natl Acad Sci U S A 93, 6731-6736.

Shehin, S. E., Stephenson, R. O. and Greenlee, W. F. (2000). Transcriptional regulation of the human CYP1B1 gene. Evidence for involvement of an aryl hydrocarbon receptor response element in constitutive expression. J Biol Chem 275, 6770-6776.

Shimada, T., Hayes, C. L., Yamazaki, H., Amin, S., Hecht, S. S., Guengerich, F. P. and Sutter, T. R. (1996). Activation of chemically diverse procarcinogens by human cytochrome P-450 1B1. Cancer Res 56, 2979-2984.

Siegle, I., Fritz, P., Eckhardt, K., Zanger, U. M. and Eichelbaum, M. (2001). Cellular localization and regional distribution of CYP2D6 mRNA and protein expression in human brain. Pharmacogenetics 11, 237-245.

Sissung, T. M., Price, D. K., Sparreboom, A. and Figg, W. D. (2006). Pharmacogenetics and regulation of human cytochrome P450 1B1: implications in hormone-mediated tumor metabolism and a novel target for therapeutic intervention. Mol Cancer Res 4, 135-150.

Sohda, T., Shimizu, M., Kamimura, S. and Okumura, M. (1993). Immunohistochemical demonstration of ethanol-inducible P450 2E1 in rat brain. Alcohol Alcohol Suppl 1B, 69-75.
Song, Z. and Pollenz, R. S. (2002). Ligand-dependent and independent modulation of aryl hydrocarbon receptor localization, degradation, and gene regulation. Molecular Pharmacology 62, 806-816.

Sutter, T. R., Tang, Y. M., Hayes, C. L., Wo, Y. Y., Jabs, E. W., Li, X., Yin, H., Cody, C. W. and Greenlee, W. F. (1994). Complete cDNA sequence of a human dioxin-inducible mRNA identifies a new gene subfamily of cytochrome P450 that maps to chromosome 2. J Biol Chem 269, 13092-13099.

Tanguay, R. L., Abnet, C. C., Heideman, W. and Peterson, R. E. (1999). Cloning and characterization of the zebrafish (Danio rerio) aryl hydrocarbon receptor. Biochim Biophys Acta 1444, 35-48.

Tanguay, R. L., Andreasen, E., Heideman, W. and Peterson, R. E. (2000). Identification and expression of alternatively spliced aryl hydrocarbon nuclear translocator 2 (ARNT2) cDNAs from zebrafish with distinct functions. Biochim Biophys Acta 1494, 117-128.

Taylor, B. L. and Zhulin, I. B. (1999). PAS domains: internal sensors of oxygen, redox potential, and light. Microbiol Mol Biol Rev 63, 479-506.

Tindberg, N. and Ingelman-Sundberg, M. (1996). Expression, catalytic activity, and inducibility of cytochrome P450 2E1 (CYP2E1) in the rat central nervous system. J Neurochem 67, 2066-2073.

Tseng, H. P. (2005). Molecular cloning and expression pattern of zebrafish cytochrome P450 genes. In Department of Life Science, vol. Ph.D (ed. Hsinchu: National Tsing-Hua University.

Tsuchiya, Y., Nakajima, M. and Yokoi, T. (2003). Critical enhancer region to which AhR/ARNT and Sp1 bind in the human CYP1B1 gene. J Biochem 133, 583-592.

Tyndale, R. F., Sunahara, R., Inaba, T., Kalow, W., Gonzalez, F. J. and Niznik, H. B. (1991). Neuronal cytochrome P450IID1 (debrisoquine/sparteine-type): potent inhibition of activity by (-)-cocaine and nucleotide sequence identity to human hepatic P450 gene CYP2D6. Mol Pharmacol 40, 63-68.

Upadhya, S. C., Tirumalai, P. S., Boyd, M. R., Mori, T. and Ravindranath, V. (2000). Cytochrome P4502E (CYP2E) in brain: constitutive expression, induction by ethanol and localization by fluorescence in situ hybridization. Arch Biochem Biophys 373, 23-34

Vidal, J. D., Vandevoort, C. A., Marcus, C. B., Lazarewicz, N. R. and Conley, A. J. (2005). 2,3,7,8-tetrachlorodibenzo-p-dioxin induces CYP1B1 expression in human luteinized granulosa cells. Arch Biochem Biophys 439, 53-60.

Walisser, J. A., Bunger, M. K., Glover, E., Harstad, E. B. and Bradfield, C. A. (2004). Patent ductus venosus and dioxin resistance in mice harboring a hypomorphic Arnt allele. Journal of Biological Chemistry 279, 16326-16331.

Walker, M. K. and Peterson, R. E. (1994a). Aquatic toxicity of dioxins and related chemicals. In Dioxins and Health, 347-387.

Walker, M. K. and Peterson, R. E. (1994b). Toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin to brook trout (Salvelinus fontinalis) during early development. Environ Toxicol Chem 113, 817-820.

Walker, N. J., Gastel, J. A., Costa, L. T., Clark, G. C., Lucier, G. W. and Sutter, T. R. (1995). Rat CYP1B1: an adrenal cytochrome P450 that exhibits sex-dependent expression in livers and kidneys of TCDD-treated animals. Carcinogenesis 16, 1319-1327.

Walker, N. J., Portier, C. J., Lax, S. F., Crofts, F. G., Li, Y., Lucier, G. W. and Sutter, T. R. (1999). Characterization of the dose-response of CYP1B1, CYP1A1, and CYP1A2 in the liver of female Sprague-Dawley rats following chronic exposure to 2,3,7,8-tetrachlo rodibenzo-p-dioxin. Toxicol Appl Pharmacol 154, 279-286.

Wang, G. L., Jiang, B. H., Rue, E. A. and Semenza, G. L. (1995). Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A 92, 5510-5514.

Wang, W. D., Wang, Y., Wen, H. J., Buhler, D. R. and Hu, C. H. (2004). Phenylthiourea as a weak activator of aryl hydrocarbon receptor inhibiting 2,3,7,8-tetrachlorodibenzo- p-dioxin-induced CYP1A1 transcription in zebrafish embryo. Biochem Pharmacol 68, 63-71
.
Warner, M., Hellmold, H., Yoshida, S., Liao, D., Hedlund, E. and Gustafsson, J. A. (1997). Cytochrome P450 in the breast and brain: role in tissue-specific activation of xenobiotics. Mutat Res 376, 79-85.

Watts, P. M., Riedl, A. G., Douek, D. C., Edwards, R. J., Boobis, A. R., Jenner, P. and Marsden, C. D. (1998). Co-localization of P450 enzymes in the rat substantia nigra with tyrosine hydroxylase. Neuroscience 86, 511-519.

Wei, Y. D., Bergander, L., Rannug, U. and Rannug, A. (2000). Regulation of CYP1A1 transcription via the metabolism of the tryptophan-derived 6-formylindolo[3,2-b]carbazole. Arch Biochem Biophys 383, 99-107.

Wentworth, J. N., Buzzeo, R. and Pollenz, R. S. (2004). Functional characterization of aryl hydrocarbon receptor (zfAHR2) localization and degradation in zebrafish (Danio rerio). Biochem Pharmacol 67, 1363-1372.

Wolf, C. J., Ostby, J. S. and Gary, L. E. (1999). Gestational exposure to 2,3,7,8-tetrachloro
dibenzo-p-dioxin (TCDD) severely alters reproductive function of female hamster offspring. Toxicological Sciences 51, 259-264.

Yengi, L. G., Xiang, Q., Pan, J., Scatina, J., Kao, J., Ball, S. E., Fruncillo, R., Ferron, G. and Roland Wolf, C. (2003). Quantitation of cytochrome P450 mRNA levels in human skin. Anal Biochem 316, 103-110.

Yin, H. C., Tseng, H. P., Chung, H. Y., Ko, C. Y., Tzou, W. S., Buhler, D. R. and Hu, C. H. (2008). Influence of TCDD on zebrafish CYP1B1 transcription during development. Toxicol Sci 103, 158-168.

Yoo, M., Ryu, H. M., Shin, S. W., Yun, C. H., Lee, S. C., Ji, Y. M. and You, K. H. (1997). Identification of cytochrome P450 2E1 in rat brain. Biochem Biophys Res Commun 231, 254-256.

Yun, S. W., Choi, E. K., Ju, W. K., Ahn, M. S., Carp, R. I., Wisniewski, H. M. and Kim, Y. S. (1998). Extensive degeneration of catecholaminergic neurons to scrapie agent 87V in the brains of IM mice. Mol Chem Neuropathol 34, 121-132.

Zodrow, J. M., Stegeman, J. J. and Tanguay, R. L. (2004). Histological analysis of acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in zebrafish. Aquat Toxicol 66, 25-38.